Q J Med 2003; 96: 380-382
© 2003 Association of Physicians
Correspondence |
Restrictive cardiomyopathy in systemic amyloidosis
Department of Cardiology, Southampton General Hospital, Southampton e-mail: davidwald{at}hotmail.com
Sir, Amyloidosis is a heterogeneous disease characterized by the deposition of an abnormal fibrillar protein (amyloid) in various tissues. Amyloid cardiomyopathy, due to amyloid infiltration of the myocardium can occur in all forms of systemic amyloid. It is a serious medical disorder with an average survival of <6 months.1 We report a case of restrictive cardiomyopathy secondary to systemic AL amyloidosis that illustrates how recent developments in diagnosis, monitoring and treatment of the disorder can substantially improve prognosis.
A 47-year-old man who had been well 6 months previously, was admitted to hospital with symptoms of breathlessness and postural hypotension. He looked unwell and undernourished, with an elevated jugular venous pressure and a positive Kussmaul's sign. There was peripheral oedema, hepatomegaly, ascites, a right-sided pleural effusion and bilateral carpal tunnel syndrome. The ECG revealed low voltage complexes and lateral T wave inversion. Echocardiography demonstrated a speckled and hypertrophied left ventricule, biatrial enlargement with evidence of left atrial appendage and right atrial thrombus (Figure 1
). Systolic function was mildly impaired and ventricular relaxation appeared stiff. Cardiac catheterization demonstrated normal coronary arteries; the right and left ventricular diastolic pressure traces showed a ‘dip and plateau wave form’ with wide separation of right and left ventricular pressures, supporting a diagnosis of a restrictive cardiomyopathy. Rectal biopsy (stained with congo red) confirmed the presence of amyloid.
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Further investigation, aimed at identifying the specific form of amyloid, demonstrated kappa light chains on electrophoresis of urine and plasma, 7% plasma cells on bone-marrow examination together with positive staining for AL amyloid on immunofixation of the rectal biopsy. A coagulation screen demonstrated factor X deficiency associated with an INR of 1.7.
Radioisotope scintigraphy using technetium-99m-labelled aprotinin confirmed AL amyloid in the myocardium (Figure 2a) and a radioiodinated serum amyloid P scintigram revealed intense hepatic and splenic uptake, confirming widespread systemic amyloidosis (Figure 2b).
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He was treated with diuretics, warfarin (despite concerns over the factor-X-related coagulopathy) and a course of chemotherapy (oral prednisolone, cyclophosphamide and i.v. melphalan) dose-adjusted to his serum free light-chain concentrations. His condition improved. By 6 months his exercise tolerance increased to half a mile, his left atrial thrombus cleared without complication, and his carpal tunnel syndrome and postural hypotension resolved.
Classification of amyloid into its various forms, by identifying the specific protein precursor is important, as this determines treatment. Hereditary and non-hereditary forms exist.1 Familial amyloid polyneuropathy is extremely rare and of the two forms of non-hereditory amyloid, primary (AL) and secondary (AA), AL amyloid is the more prevalent, in which the precursor is a monoclonal immunoglobulin light chain, related to multiple myeloma.
The gold standard for diagnosing cardiac amyloid is cardiac biopsy, which carries a procedure-related morbidity. This was avoided in our case by two non-invasive imaging techniques using radioactively-labelled proteins that specifically bind to amyloid deposits. Aprotinin (an anti-serine protease) is naturally cleared in the liver, spleen and kidneys; uptake in other tissues, particularly the myocardium, is sensitive for detecting AL amyloid.2 Serum amyloid P (SAP), a plasma protein, binds reversibly to amyloid fibrils; radioiodinated SAP scintigraphy provides whole body imaging, enabling the quantitative detection of amyloid deposits in all tissues.3
Cardiac amyloid complicates up to 90% of AL amyloidosis and is the presenting problem in about one third. Stiffened ventricular relaxation (diastolic dysfunction) is the early echocardiographic hallmark with biventricular failure dominated by right-sided signs and symptoms. Diastolic heart failure is typically refractory to standard treatments of left ventricular systolic dysfunction. Diuretics are the mainstay of treatment but must be used cautiously, as hypovolaemia worsens a predisposition to postural hypotension.
Reducing the concentration of the precursor immunoglobulin light chain with chemotherapy is central to improving prognosis in AL amyloid. Traditional approaches aimed at entirely suppressing the plasma cell dyscrasia together with insensitive methods of disease monitoring have resulted in significant treatment-related mortality.4 A new immunoassay that measures circulating serum free light chains largely overcomes this problem by providing a method for following the response to chemotherapy, guiding dose adjustment and avoiding complications of treatment. Lachmann and colleagues have shown that achieving a 50% or greater reduction in serum light chain concentration is associated with a favourable prognosis; an 88% five-year survival, regardless of the treatment regimen or starting serum free light chain levels5—additional treatment to achieve further light-chain reductions was unnecessary. Figure 3 shows the fall in serum free light-chain level with treatment over time in this case, and how the use of chemotherapy was minimized.
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With the availability of non-invasive diagnostic imaging and serum light-chain analysis, expectations of a universally poor survival in amyloid heart disease can now be revised. These developments also raise the possibility of screening for AL amyloid in echocardiographically identified diastolic dysfunction; a potentially reversible cause of diastolic heart failure.
Acknowledgments
We thank Helen Lachmann for providing images and data for the preparation of this report.
References
1. Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol 1995; 32:45–59.[Web of Science][Medline]
2. Aprile C, Marinone G, Sapanaro R, Bonino C, Melini G. Cardiac and pleuropulmonary AL amyloid imaging with technetium-99m labelled aprotinin. Eur J Nuc Med 1995; 22:1393–401.[CrossRef][Medline]
3. Hawkins PN, Lavender JP, Pepys MB. Evaluation of systemic amyloidosis by scintigraphy with 123T-labelled serum amyloid P component. N Engl J Med 1990; 323:508–13.[Abstract]
4. Gertz MA, Kyle RA, Greipp PR. Response rates and survival in primary systemic amyloidosis. Blood 1991; 77:257–62.
5. Lachmann H, Gallimore R, Gillmore JD, Smith L, Bradwell AR, Hawkins PN. Outcome of patients with systemic amyloidosis in relation to concentration of a circulating free immunoglobulin light chain. Br J Haematol 2002; 117(suppl. 1):95.
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